tbuckley/cabot-search huggingface dataset:
Dietary Carotenoids, Vitamins A, C, and E, and Advanced Age-Related Macular Degeneration
Authors: Johanna M. Seddon
Journal: JAMA (1994)

<h3>Objective.</h3> —To evaluate the relationships between dietary intake of carotenoids and vitamins A, C, and E and the risk of neovascular age-related macular degeneration (AMD), the leading cause of irreversible blindness among adults. <h3>Design.</h3> —The multicenter Eye Disease Case-Control Study. <h3>Setting.</h3> —Five ophthalmology centers in the United States. <h3>Patients.</h3> —A total of 356 case subjects who were diagnosed with the advanced stage of AMD within 1 year prior to their enrollment, aged 55 to 80 years, and residing near a participating clinical center. The 520 control subjects were from the same geographic areas as case subjects, had other ocular diseases, and were frequency-matched to cases according to age and sex. <h3>Main Outcome Measures.</h3> —The relative risk for AMD was estimated according to dietary indicators of antioxidant status, controlling for smoking and other risk factors, by using multiple logistic-regression analyses. <h3>Results.</h3> —A higher dietary intake of carotenoids was associated with a lower risk for AMD. Adjusting for other risk factors for AMD, we found that those in the highest quintile of carotenoid intake had a 43% lower risk for AMD compared with those in the lowest quintile (odds ratio, 0.57; 95% confidence interval, 0.35 to 0.92;<i>P</i>for trend=.02). Among the specific carotenoids, lutein and zeaxanthin, which are primarily obtained from dark green, leafy vegetables, were most strongly associated with a reduced risk for AMD (<i>P</i>for trend=.001). Several food items rich in carotenoids were inversely associated with AMD. In particular, a higher frequency of intake of spinach or collard greens was associated with a substantially lower risk for AMD (<i>P</i>for trend&lt;.001). The intake of preformed vitamin A (retinol) was not appreciably related to AMD. Neither vitamin E nor total vitamin C consumption was associated with a statistically significant reduced risk for AMD, although a possibly lower risk for AMD was suggested among those with higher intake of vitamin C, particularly from foods. <h3>Conclusion.</h3> —Increasing the consumption of foods rich in certain carotenoids, in particular dark green, leafy vegetables, may decrease the risk of developing advanced or exudative AMD, the most visually disabling form of macular degeneration among older people. These findings support the need for further studies of this relationship. (<i>JAMA</i>. 1994;272:1413-1420)
A Hidden Crisis
Authors: Sadie T. Velasquez, James Cleveland, David O. Diaz, Diane Ferguson, Rebecca Moote, Kathryn Parke, Bridgett Piernik-Yoder, George Folz, Joseph A. Zorek
Journal: New England Journal of Medicine (2022)

Mr. Banks' dementia has progressed to the point where he needs constant supervision. But when his daughter takes on his care, she suffers her own crisis.
Product Hopping in the Drug Industry — Lessons from Albuterol
Authors: Olivier J. Wouters, William B. Feldman, S. Sean Tu
Journal: New England Journal of Medicine (2022)

Product hops to albuterol inhalers containing hydrofluoroalkane rather than chlorofluorocarbons cost payers and patients billions of dollars. Without patent and regulatory reform, this pattern is likely to be repeated.
Matrix Metalloproteinases in Vascular Remodeling and Atherogenesis
Authors: Zorina S. Galis, Jaikirshan J. Khatri
Journal: Circulation Research (2002)

Vascular remodeling, defined as any enduring change in the size and/or composition of an adult blood vessel, allows adaptation and repair. On the other hand, inappropriate remodeling, including its absence, underlies the pathogenesis of major cardiovascular diseases, such as atherosclerosis and restenosis. Since degradation of the extracellular matrix scaffold enables reshaping of tissue, participation of specialized enzymes called matrix metalloproteinases (MMPs) has become the object of intense recent interest in relation to physiological (“good”) and pathological (“bad”) vascular remodeling. Experimental evidence acquired in vitro and in vivo suggests that the major drivers of vascular remodeling, hemodynamics, injury, inflammation, and oxidative stress, regulate MMP expression and activity. Alternatively, nonspecific MMP inhibition seems to oppose remodeling, as suggested by the inhibition of intimal thickening and outward arterial remodeling. An emerging concept is that MMP-related genetic variations may contribute to heterogeneity in the presentation and natural history of atherosclerosis. The hypothesis that MMPs contribute to weakening of atherosclerotic plaques is especially attractive for the potential development of therapeutic interventions aimed at preventing plaque disruption (“the ugly”), a major cause of acute cardiovascular events. However, the current lack of appropriate experimental tools, including availability of specific MMP inhibitors and pertinent animal models, still limits our understanding of the many actions and relative contributions of specific MMPs. Our future potential ability to control vascular remodeling via regulation of MMPs will also depend on reaching a consensus of what is indeed “good” or “bad” vascular remodeling, concepts that have continued to evolve and change.
Efficacy of a Mass Hepatitis B Vaccination Program in Taiwan
Authors: Hsu-Mei Hsu
Journal: JAMA (1988)

To evaluate the efficacy of the mass hepatitis B vaccination program in Taiwan in interrupting perinatal hepatitis B virus transmission, 3464 randomly selected 18-month-old infant vaccinees born to hepatitis B surface antigen—carrier mothers were recruited from 9697 eligible infants during a six-month period of the program. They were divided into ten groups according to maternal infectivity and compliance with the vaccination schedule. Serum samples were tested for hepatitis B surface antigen, antibody to hepatitis B surface antigen, and antibody to hepatitis B core antigen. In 786 infants who had highly infectious mothers and who received hepatitis B immune globulin and vaccine on schedule, the protective efficacy was about 85%. The efficacy seemed to be slightly lower in those immunized off schedule. Overall, 11% of infants still carried hepatitis B surface antigen, and 81% of the infants had antibody to hepatitis B surface antigen that exceeded 10 mlU/mL in more than 90% of them. The geometric mean titers of antibody to hepatitis B surface antigen were more than 200 mlU/mL in every group of infants. We conclude that the mass vaccination program is efficacious in preventing perinatal hepatitis B virus transmission and the chronic carrier state; most infant vaccinees have adequate levels of protective antibody at 18 months of age. This program is extremely significant in the control of hepatitis B virus infection in Taiwan. (<i>JAMA</i>1988;260:2231-2235)
Sexual dysfunction in female hemodialysis patients: A multicenter study
Authors: Yu-Sen Peng, Chih-Kang Chiang, Tze-Wah Kao, Kung-Yu Hung, Chia-Sheng Lu, Shou-Shang Chiang, Chwei-Shiun Yang, Yu-Chin Huang, Kwan-Dun Wu, Ming-Shiou Wu, Yih-Ron Lien, Chin-Ching Yang, Dong-Ming Tsai, Pei-Yuan Chen, Cheng-Shiung Liao, Tun-Jun Tsai, Wang-Yu Chen
Journal: Kidney International (2005)
Expression of Toll-Like Receptors in Human Atherosclerotic Lesions
Authors: Kristina Edfeldt, Jesper Swedenborg, Göran K. Hansson, Zhong-qun Yan
Journal: Circulation (2002)

Background — Innate immune reactions against bacteria and viruses have been implicated in the pathogenesis of atherosclerosis. To explore the molecular mechanism by which microbe recognition occurs in the artery wall, we characterized the expression of toll-like receptors (TLRs), a family of pathogen pattern recognition receptors, in atherosclerotic lesions. Methods and Results — Semiquantitative polymerase chain reaction and immunohistochemical analysis demonstrated that of 9 TLRs, the expression of TLR1, TLR2, and TLR4 was markedly enhanced in human atherosclerotic plaques. A considerable proportion of TLR-expressing cells were also activated, as shown by the nuclear translocation of nuclear factor-κB. Conclusion — Our findings illustrate a repertoire of TLRs associated with inflammatory activation in human atherosclerotic lesions, and they encourage further exploration of innate immunity in the pathogenesis of atherosclerosis.
Progression of Polypoidal Lesions Associated with Exudative Recurrence in Polypoidal Choroidal Vasculopathy
Authors: Qiyu Bo, Min Zhang, Jieqiong Chen, Huixun Jia, Mengxi Shen, Mengsha Sun, Mengqiao Xu, Jingyang Feng, Quan Yan, Yang Yu, Peirong Huang, Tong Li, Fenghua Wang, Philip J Rosenfeld, Xiaodong Sun
Journal: Ophthalmology (2022)
A double-blind randomized placebo-controlled trial of albumin in outpatients with hepatic encephalopathy: HEAL study
Authors: Andrew Fagan, Edith A Gavis, Mary Leslie Gallagher, Travis Mousel, Brian Davis, Puneet Puri, Richard K Sterling, Velimir A Luketic, Hannah Lee, Scott C Matherly, Arun J Sanyal, R Todd Stravitz, Vaishali Patel, Mohammad S Siddiqui, Amon Asgharpour, Michael Fuchs, Leroy Thacker, Jasmohan S Bajaj
Journal: Journal of Hepatology (2022)
Spray drying siRNA-lipid nanoparticles for dry powder pulmonary delivery
Authors: Christoph M. Zimmermann, Domizia Baldassi, Karen Chan, Nathan B.P. Adams, Alina Neumann, Diana Leidy Porras-Gonzalez, Xin Wei, Nikolaus Kneidinger, Mircea Gabriel Stoleriu, Gerald Burgstaller, Dominik Witzigmann, Paola Luciani, Olivia M. Merkel
Journal: Journal of Controlled Release (2022)
Assessment of portal hypertension severity using machine learning models in patients with compensated cirrhosis
Authors: Jiří Reiniš, Oleksandr Petrenko, Benedikt Simbrunner, Benedikt S. Hofer, Filippo Schepis, Marco Scoppettuolo, Dario Saltini, Federica Indulti, Tomas Guasconi, Agustin Albillos, Luis Téllez, Càndid Villanueva, Anna Brujats, Juan Carlos Garcia-Pagan, Valeria Perez-Campuzano, Virginia Hernández-Gea, Pierre-Emmanuel Rautou, Lucile Moga, Thomas Vanwolleghem, Wilhelmus J. Kwanten, Sven Francque, Jonel Trebicka, Wenyi Gu, Philip G. Ferstl, Lise Lotte Gluud, Flemming Bendtsen, Søren Møller, Stefan Kubicek, Mattias Mandorfer, Thomas Reiberger
Journal: Journal of Hepatology (2022)
Stable amorphous solid dispersion of flubendazole with high loading via electrospinning
Authors: Jana Becelaere, Elias Van Den Broeck, Ella Schoolaert, Valérie Vanhoorne, Joachim F.R. Van Guyse, Maarten Vergaelen, Sander Borgmans, Karolien Creemers, Veronique Van Speybroeck, Chris Vervaet, Richard Hoogenboom, Karen De Clerck
Journal: Journal of Controlled Release (2022)
Effect of variants in LGP2 on MDA5-mediated activation of interferon response and suppression of hepatitis D virus replication
Authors: Nadine Gillich, Zhenfeng Zhang, Marco Binder, Stephan Urban, Ralf Bartenschlager
Journal: Journal of Hepatology (2022)

Retinoic acid inducible gene I (RIG-I)-like receptors (RLRs), including RIG-I, melanoma differentiation-associated protein 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2), sense viral RNA to induce the antiviral interferon (IFN) response. LGP2, unable to activate the IFN response itself, modulates RIG-I and MDA5 signalling. HDV, a small RNA virus causing the most severe form of viral hepatitis, is sensed by MDA5. The mechanism underlying IFN induction and its effect on HDV replication is unclear. Here, we aimed to unveil the role of LGP2 and clinically relevant variants thereof in these processes. RLRs were depleted in HDV susceptible HepaRGNTCP cells and primary human hepatocytes. Cells were reconstituted to express different LGP2 versions. HDV and IFN markers were quantified in a time-resolved manner. Interaction studies among LGP2, MDA5, and RNA were performed by pull-down assays. LGP2 is essential for the MDA5-mediated IFN response induced upon HDV infection. This induction requires both RNA binding and ATPase activities of LGP2. The IFN response only moderately reduced HDV replication in resting cells but profoundly suppressed cell division-mediated HDV spread. An LGP2 variant (Q425R), predominating in Africans who develop less severe chronic hepatitis D, mediated detectably higher basal and faster HDV-induced IFN response as well as stronger HDV suppression. Mechanistically, LGP2 RNA binding was a prerequisite for the formation of stable MDA5-RNA complexes. MDA5 binding to RNA was enhanced by the Q425R LGP2 variant. LGP2 is essential to mount an antiviral IFN response induced by HDV and stabilises MDA5-RNA interaction required for downstream signalling. The natural Q425R LGP2 is a gain-of-function variant and might contribute to an attenuated course of hepatitis D. HDV is the causative pathogen of chronic hepatitis D, a severe form of viral hepatitis that can lead to cirrhosis and hepatocellular carcinoma. Upon infection, the human immune system senses HDV and mounts an antiviral interferon (IFN) response. Here, we demonstrate that the immune sensor LGP2 cooperates with MDA5 to mount an IFN response that represses HDV replication. We mapped LGP2 determinants required for IFN system activation and characterised several natural genetic variants of LGP2. One of them reported to predominate in sub-Saharan Africans can accelerate HDV-induced IFN responses, arguing that genetic determinants, possibly including LGP2, might contribute to slower disease progression in this population. Our results will hopefully prompt further studies on genetic variations in LGP2 and other components of the innate immune sensing system, including assessments of their possible impact on the course of viral infection.
Clinical characterization and treatment outcomes of follicular cutaneous immune–related adverse events caused by immune checkpoint inhibitors: A multicenter retrospective study
Authors: Azael Freites-Martinez, Vasiliki Nikolaou, Konstantinos Lallas, Cristina Carrera, Pietro Sollena, Zoe Apalla, Michela Starace, Davide Fattore, Gabriella Fabbrocini, Sonia Segura, Julia Riganti, Vincent Sibaud
Journal: Journal of the American Academy of Dermatology (2022)
Widespread exposure to Crimean-Congo haemorrhagic fever in Uganda might be driven by transmission from Rhipicephalus ticks: Evidence from cross-sectional and modelling studies
Authors: Swaib A. Lule, Rory Gibb, Dennison Kizito, Gladys Nakanjako, Joseph Mutyaba, Stephen Balinandi, Leah Owen, Kate E. Jones, Ibrahim Abubakar, Julius J. Lutwama, Nigel Field
Journal: Journal of Infection (2022)
Engineered biomimetic nanoreactor for synergistic photodynamic-chemotherapy against hypoxic tumor
Authors: Haoyu Guo, Lutong Wang, Wei Wu, Mingke Guo, Lingkai Yang, Zhenhao Zhang, Li Cao, Feifei Pu, Xin Huang, Zengwu Shao
Journal: Journal of Controlled Release (2022)

Photodynamic therapy (PDT) can produce a large amount of reactive oxygen species (ROS) in the radiation field to kill tumor cells. However, the sustainable anti-tumor efficacy of PDT is limited due to the hypoxic microenvironment of tumor. In this study, classic PDT agent indocyanine green (ICG) and hypoxia-activated chemotherapeutic drug tirapazamine (TPZ) were loaded on mesoporous polydopamine (PDA) to construct [email protected] nanoparticles (PIT). Then, PIT was camouflaged with cyclic arginine-glycine-aspartate (cRGD) modified tumor cell membranes to obtain the engineered membrane-coated nanoreactor (cRGD-mPIT). The nanoreactor cRGD-mPIT could achieve the dual-targeting ability via tumor cell membrane mediated homologous targeting and cRGD mediated active targeting. With the enhanced tumor-targeting and penetrating delivery system, PIT could efficiently accumulate in hypoxic tumor cells and the loaded drugs were quickly released in response to near-infrared (NIR) laser. The nanoreactor might produce cytotoxic ROS under NIR and further enhance hypoxia within tumor to activate TPZ, which efficiently inhibited hypoxic tumor by synergistic photodynamic-chemotherapy. Mechanically, hypoxia-inhibitory factor-1α (HIF-1α) was down-regulated by the synergistic therapy. Accordingly, the cRGD-mPIT nanoreactor with sustainable and cascade anti-tumor effects and satisfied biosafety might be a promising strategy in hypoxic tumor therapy.
Clinical features, outcomes, and HLA risk factors associated with nitrofurantoin-induced liver injury
Authors: Naga Chalasani, Yi-Ju Li, Andrew Dellinger, Victor Navarro, Herbert Bonkovsky, Robert J. Fontana, Jiezhun Gu, Huiman Barnhart, Elizabeth Phillips, Craig Lammert, Tae-Hwi Schwantes-An, Paola Nicoletti, David E. Kleiner, Jay H. Hoofnagle
Journal: Journal of Hepatology (2022)
Activity of menin inhibitor ziftomenib (KO-539) as monotherapy or in combinations against AML cells with MLL1 rearrangement or mutant NPM1
Authors: Warren Fiskus, Naval Daver, Steffen Boettcher, Christopher P. Mill, Koji Sasaki, Christine E. Birdwell, John A. Davis, Kaberi Das, Koichi Takahashi, Tapan M. Kadia, Courtney D. DiNardo, Francis Burrows, Sanam Loghavi, Joseph D. Khoury, Benjamin L. Ebert, Kapil N. Bhalla
Journal: Leukemia (2022)

In MLL1-rearranged AML (MLL1-r), the MLL1 fusion protein (MLL-FP) causes dysregulated expression of HOXA9, MEIS1, PBX3, MEF2C and CDK6 [1,2].HOXA9 and its co-factor MEIS1 are leukemogenic in myeloid stem progenitor cells [3][4][5].Additionally, in AML with mtNPM1 (NPM1c), MLL1 is the main oncogenic regulator of HOXA9, MEIS1 and FLT3, promoting self-renewal of myeloid progenitor cells [2,6,7].Orally bioavailable, investigational or clinical drug candidate Menin inhibitors (MIs) disrupt binding of Menin to its binding pocket in MLL1/2 and MLL1-FP, which reduces MLL1/2 and MLL1-FP binding to their targets, inhibits HOXA9/MEIS1 activity, represses PBX3, MEF2C, FLT3 and CDK6, as well as induces differentiation and loss of survival of AML with MLL1-r or with mutant (mt)-NPM1 [2, 8-10].In early clinical trials, monotherapy with MI is well tolerated and has achieved objective remissions in patients with previously treated relapsed/ refractory AML harboring MLL1-r or NPM1c [2,11].However, most patients either fail to respond or eventually relapse [11].Therefore, there is a need to investigate the activity of additional MIs and MIbased combinations that may exhibit superior activity and prevent or abrogate MI-resistance in AML cells with MLL1-r or mtNPM1.Here, we determined that exposure for 4 days to the orally bioavailable, investigational, MI ziftomenib (KO-539) dosedependently inhibited cell growth of MOLM13 (expressing MLL1-AF9) and OCI-AML3 cells (expressing mtNPM1, DNMT3A R882C and homozygous activating NRAS-Q61L mutations) (Supplementary Figs.S1A andS1B).Ziftomenib treatment for 7 days induced expression of the myeloid differentiation marker CD11b and increased morphologic features of differentiation (Fig. 1A, Supplementary Figs.S1C andS1D) [10].Treatment with ziftomenib for 4 days dose-dependently induced loss of viability in OCI-AML3 and MV4-11 cells, but less so in MOLM13 and was ineffective in THP1 or NOMO-1 cells (Fig. 1B and Supplementary Figs.S1B-S1E).Ziftomenib treatment reduced mRNA levels of MEIS1, PBX3, MYC, FLT3, CDK6 and BCL2, while inducing mRNA levels of CD11b (Supplementary Figs.S2A andS2B).Notably, ziftomenib also
Fate of Research Studies
Authors: P J Easterbrook, D R Matthews
Journal: Journal of the Royal Society of Medicine (1992)

A retrospective survey was conducted of 720 research protocols, approved by the Central Oxford Research Ethics Committee between 1984 and 1987, to determine the fate of research studies from inception. Forty-five per cent were clinical trials, 23% were observational studies and 32% were laboratory-based experimental studies. Further informationwasobtained on 487 studies, of which 287 (59%) had been completed, 100 (21%) had never started, 58 (12%) had been abandoned or were in abeyance and 42 (9%) were still ongoing, as of May 1990. Forty-three per cent of the original 487 studies were subsequently published or presented. The most frequent reason for not starting a study was failure to obtain funding (40%). The main reason for abandoning a study was difficulty in recruiting study participants (28%). Departure of one of the investigators from the institution and a variety of logistical problems were also common reasons for either not starting or abandoning a study. A thorough review of the pragmatic as well as the scientific aspects of a planned research project is important to minimize the initiation of studies that are unlikely to succeed.
Patient satisfaction with outpatient hysteroscopy versus day case hysteroscopy: randomised controlled trial
Authors: C. Kremer
Journal: BMJ (2000)

Objective: To compare outpatient hysteroscopy with day case hysteroscopy in terms of patient satisfaction and acceptability Setting: Gynaecology clinic of a teaching hospital. Participants: 100 women. Design and interventions: Patients were randomly allocated to outpatient hysteroscopy or day case hysteroscopy provided they had no preference for either procedure. Main outcome measures: Satisfaction rate, requirements for postoperative analgesia, speed of recovery, time away from home, and time off work Results: The outpatient group recovered preoperative fitness more quickly than the day case group (2 days (range 1-2.7) versus 3 days (2–4), P<0.05). After the procedure, the outpatient group were also fully mobile more quickly than the day case group (0 minutes (0–5) versus 105 minutes (80–120), P<0.001). Requirements for postoperative analgesia were similar in both groups. Overall, 78% of patients considered that the pain from outpatient hysteroscopy was less than that usually experienced during menstruation. Patient satisfaction was similar in both groups (83.6% in the outpatient group versus 77.0% in the day case group). Conclusions: Outpatient hysteroscopy and day case hysteroscopy were equally acceptable to patients. Patients recovered significantly more quickly from outpatient hysteroscopy than from day case hysteroscopy. #### Key messages
Venous thromboembolism with JAK inhibitors and other immune-modulatory drugs: a Swedish comparative safety study among patients with rheumatoid arthritis
Authors: Viktor Molander, Hannah Bower, Thomas Frisell, Benedicte Delcoigne, Daniela Di Giuseppe, Johan Askling
Journal: Annals of the Rheumatic Diseases (2022)

To assess and compare the incidence of venous thromboembolism (VTE) in patients with rheumatoid arthritis (RA) treated with Janus kinase inhibitors (JAKi), tumour necrosis factor inhibitors (TNFi) or other biological disease modifying antirheumatic drugs (bDMARDs). For contextualisation, to assess VTE incidences in the Swedish general population and in the RA source population.We performed a nationwide register-based, active comparator, new user design cohort study in Sweden from 2010 to 2021. The Swedish Rheumatology Quality Register was linked to national health registers to identify treatment cohorts (exposure) of initiators of a JAKi, a TNFi, or a non-TNFi bDMARD (n=32 737 treatment initiations). We also identified a general population cohort (matched 1:5, n=92 108), and an 'overall RA' comparator cohort (n=85 722). Outcome was time to first VTE during the follow-up, overall and by deep vein thrombosis (DVT) and pulmonary embolism (PE). We calculated incidence rates (IR) and multivariable-adjusted HRs using Cox regression.Based on 559 incident VTE events, the age- and sex-standardised (to TNFi) IR (95% CI) for VTE was 5.15 per 1000 person-years (4.58 to 5.78) for patients treated with TNFi, 11.33 (8.54 to 15.04) for patients treated with JAKi, 5.86 (5.69 to 6.04) in the overall RA cohort and 3.28 (3.14 to 3.43) in the general population. The fully adjusted HR (95% CI) for VTE with JAKi versus TNFi was 1.73 (1.24 to 2.42), the corresponding HR for PE was 3.21 (2.11 to 4.88) and 0.83 (0.47 to 1.45) for DVT.Patients with RA treated with JAKi in clinical practice are at increased risk of VTE compared with those treated with bDMARDs, an increase numerically confined to PE.